Perinatal Institute, Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Center for Stem Cell and Organoid Medicine (CuSTOM), Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Nat Cardiovasc Res. 2024 Aug;3(8):933-950. doi: 10.1038/s44161-024-00510-3. Epub 2024 Jul 24.
Valve remodeling is a process involving extracellular matrix organization and elongation of valve leaflets. Here, through single-cell RNA sequencing of human fetal valves, we identified an elastin-producing valve interstitial cell (VIC) subtype (apolipoprotein E (APOE), elastin-VICs) spatially located underneath valve endothelial cells (VECs) sensing unidirectional flow. APOE knockdown in fetal VICs resulted in profound elastogenesis defects. In valves with pulmonary stenosis (PS), we observed elastin fragmentation and decreased expression of APOE along with other genes regulating elastogenesis. Cell-cell interaction analysis revealed that jagged 1 (JAG1) from unidirectional VECs activates elastogenesis in elastin-VICs through NOTCH2. Similar observations were made in VICs cocultured with VECs under unidirectional flow. Notably, a drastic reduction of JAG1-NOTCH2 was also observed in PS valves. Lastly, we found that APOE controls JAG1-induced NOTCH activation and elastogenesis in VICs through the extracellular signal-regulated kinase pathway. Our study suggests important roles of both APOE and NOTCH in regulating elastogenesis during human valve remodeling.
瓣膜重塑是一个涉及细胞外基质组织和瓣膜小叶伸长的过程。在这里，通过对人类胎儿瓣膜的单细胞 RNA 测序，我们鉴定出一种弹性蛋白产生的瓣膜间质细胞（VIC）亚型（载脂蛋白 E（APOE），弹性蛋白-VIC），其空间位置位于感应单向流的瓣膜内皮细胞（VEC）下方。在胎儿 VIC 中敲低 APOE 会导致严重的弹性蛋白生成缺陷。在肺动脉瓣狭窄（PS）的瓣膜中，我们观察到弹性蛋白碎片化和 APOE 及其它调节弹性蛋白生成的基因表达下调。细胞间相互作用分析表明，单向 VEC 中的锯齿 1（JAG1）通过 NOTCH2 激活弹性蛋白-VIC 中的弹性蛋白生成。在单向流条件下与 VEC 共培养的 VIC 中也观察到类似的现象。值得注意的是，在 PS 瓣膜中也观察到 JAG1-NOTCH2 的急剧减少。最后，我们发现 APOE 通过细胞外信号调节激酶途径控制 JAG1 诱导的 NOTCH 激活和 VIC 中的弹性蛋白生成。我们的研究表明，APOE 和 NOTCH 在人类瓣膜重塑过程中的弹性蛋白生成中都起着重要作用。
